title: MUS81 promotes common fragile site expression.
abstract: Fragile sites are chromosomal loci with a propensity to form gaps or breaks during early mitosis, and their instability is implicated as being causative in certain neurological disorders and cancers. Recent work has demonstrated that the so-called common fragile sites (CFSs) often impair the faithful disjunction of sister chromatids in mitosis. However, the mechanisms by which CFSs express their fragility, and the cellular factors required to suppress CFS instability, remain largely undefined. Here, we report that the DNA structure-specific nuclease MUS81-EME1 localizes to CFS loci in early mitotic cells, and promotes the cytological appearance of characteristic gaps or breaks observed at CFSs in metaphase chromosomes. These data indicate that CFS breakage is an active, MUS81-EME1-dependent process, and not a result of inadvertent chromatid rupturing during chromosome condensation. Moreover, CFS cleavage by MUS81-EME1 promotes faithful sister chromatid disjunction. Our findings challenge the prevailing view that CFS breakage is a nonspecific process that is detrimental to cells, and indicate that CFS cleavage actually promotes genome stability.
authors.affiliation: Weatherall Institute of Molecular Medicine, Department of Oncology, University of Oxford, Oxford OX3 9DS, UK. yings@zju.edu.cn
authors.forename: Songmin
authors.initials: S
authors.lastname: Ying
authors.forename: Sheroy
authors.initials: S
authors.lastname: Minocherhomji
authors.forename: Kok Lung
authors.initials: KL
authors.lastname: Chan
authors.forename: Timea
authors.initials: T
authors.lastname: Palmai-Pallag
authors.forename: Wai Kit
authors.initials: WK
authors.lastname: Chu
authors.forename: Theresa
authors.initials: T
authors.lastname: Wass
authors.forename: Hocine W
authors.initials: HW
authors.lastname: Mankouri
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Ian D
authors.initials: ID
authors.lastname: Hickson
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D043283:Chromosome Fragile Sites / Q000235:genetics*; D020090:Chromosome Segregation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004706:Endodeoxyribonucleases / Q000378:metabolism; D004720:Endonucleases / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D042822:Genomic Instability; D006801:Humans; D016133:Polymerase Chain Reaction
chemical_list: D004268:DNA-Binding Proteins; C507947:Eme1 protein, human; D004706:Endodeoxyribonucleases; D004720:Endonucleases; C498772:MUS81 protein, human